Tuberculosis (TB) is one of the most common infectious diseases worldwide. Due to the multi-drug resistance of M. tuberculosis (Mtb) and the low efficiency of BCG vaccination in adults, new strategies are required to prevent TB epidemics. To develop such strategies it is important to understand the exact mechanisms that distinguish protective vs pathological reactivity of the host, underlie the establishment of latent vs active TB, and determine the rate of TB progression. The project is focused on the mechanisms that control TB progression. Recent observations suggest that TB progression is associated with: (i) high lung expression of the immunoregulatory cytokine IL-11; (ii) high lung expression of the pro-inflammatory factors IL-12, IL-6, MIP- 11, MIP-12, and MIP-2; (iii) a decrease in the frequency of fully differentiated CD27low CD4 T cells in the lungs, an indicator of incomplete T-cell differentiation. Of these factors, IL-12 and IL-11 are the best predictors of TB progression. One of these factors, cytokine IL-11, has never been studied in connection with TB pathogenesis. The goal of the project is to explore mechanisms whereby IL-11 contributes to TB pathology, search for genetic factors controlling IL-11 expression, and address the impact of IL-11 and other inflammation-related factors in the pathogenesis of TB in humans. The studies will, first, explore whether and how IL-11 modifies phagocyte reactivity to Mtb and differentiation of Th1 cells during TB. Effects of IL-11 and its neutralization on the transcriptional responses of and signaling pathways activation in TB- susceptible and TB-resistant phagocytes infected with Mtb will be evaluated in vitro. Effects of IL-11 and its neutralization on the progression of TB and Th1 cell differentiation will be addressed in vivo. Second, the project will search for gene loci that control the expression of IL-11 and other inflammation-related factors during TB. These studies will be performed in (A/Sn x I/St)F2 mice that display different susceptibility to TB and different levels of IL-11 expression. Third, expression of IL-11, several pro-inflammatory factors, and the degree of CD4 T cell differentiation will be evaluated in patients with different clinical forms of pulmonary TB. Altogether, the proposed studies will result in a deeper understanding of TB pathogenesis and identify new biomarkers that may be used to predict TB severity, monitor TB patients and their responsiveness to treatment, and serve as potential targets for TB immunomodulation.